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Australasian Journal of Dermatology (2014) ••, ••–••

doi: 10.1111/ajd.12191

REVIEW ARTICLE

Phototherapy for the treatment of cutaneous graft versus host disease Kieran B. Garbutcheon-Singh1,2 and Pablo Fernández-Peñas1,2 1

Department of Dermatology, Westmead Hospital, Westmead, and 2Sydney Medical School-Westmead, The University of Sydney, Sydney, New South Wales, Australia

ABSTRACT Graft versus host disease (GvHD) occurs in half the patients who receive allogenic haematopoietic stem cell transplantation and is a major contributor for the morbidity and mortality in these patients. Immunosuppressant therapy cannot suppress all the manifestations of GvHD and new ways of treating the condition are needed. The focus of this review is the treatment of cutaneous GvHD through phototherapy. Of the six acute and ten chronic cutaneous GvHD case series examined the overall trend was that phototherapy was able to reduce the presence of cutaneous lesions of GvHD and, as a consequence, steroid use could be reduced. This provides a positive outlook for phototherapy as a treatment for cutaneous GvHD but there is a need for future studies to include larger numbers of patients in order to obtain more data. Key words: cutaneous graft versus host disease, phototherapy.

INTRODUCTION In 2006 there were a total of 50 417 first time haematopoietic stem cell transplantations, with most of such transplantations taking place in Europe, America and Australia (≥300 per capita per 10 million).1 A substantial contribution to the mortality and morbidity of most (around 50%) patients who undergo haematopoietic stem cell transplantation is through the development of a condition known as graft versus host disease (GvHD).2 Patients who develop

Correspondence: Dr Pablo Fernández-Peñas, Department of Dermatology, Westmead Hospital, Westmead, NSW 2145, Australia. Email: [email protected] Kieran B. Garbutcheon-Singh, Medical Student. Pablo FernándezPeñas, FACD. Conflict of interest: none. Submitted 10 November 2013; accepted 8 March 2014. © 2014 The Australasian College of Dermatologists

GvHD can have several organs affected, but most frequently the condition presents on the skin. For patients with cutaneous GvHD the standard treatment is immunosuppressive therapy, which is effective in some cases, whereas topical treatments are less effective except in localized GvHD.3,4 As the skin is the most commonly affected organ in patients suffering GvHD there is a great need for supportive therapies.

GRAFT VERSUS HOST DISEASE Cutaneous GvHD can be classified in three different forms after careful clinical-pathological correlation5,6: acute GvHD, chronic lichenoid GvHD and chronic sclerodermatous GvHD. Although acute GvHD tends to appear earlier than the other forms,7 timing after transplant cannot be the sole criterion for classifying GvHD.6

Acute GvHD Just after stem cell transplantation the main complication is acute GvHD. There is a 50% mortality rate in patients with a moderate to severe form of acute GvHD. The diagnosis of acute GvHD needs the correlation of cutaneous findings together with suggestive pathology findings. Clinically, acute GvHD is a maculopapular exanthema, sometimes scarlatiniform, similar to a cutaneous drug reaction or a viral exanthema. The differential diagnosis has been recently reviewed.6 The five major sites for acute GvHD are the liver, lung, lymphoid tissue, the gastrointestinal tract and, the most frequently involved tissue, the skin.8 Some studies insist that cutaneous manifestations indicate a worse prognosis for patients.9 In contrast to this, other studies have found that the rates of survival were similar in patients who had only

Abbreviations: BBUVB CR GvHD HLA NBUVB

broadband UVB complete response graft versus host disease human leukocyte antigen narrowband UVB

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KB Garbutcheon-Singh and P Fernández-Peñas

cutaneous involvement and patients who have multiple organ involvement.10 Other studies indicated that a better prognosis was seen in patients who presented with acute GvHD limited to the skin.11 The involvement of the gastrointestinal tract, liver and skin are used in grading the severity of acute GvHD.4 A variety of risk factors has been linked to the development of acute GvHD. These risk factors include mismatching human leukocyte antigens (HLA), chronic myeloid leukaemia as the initial diagnosis, multiple stem cell transplants and the exposure of the whole body to radiotherapy or the administration of prophylactic immunosuppressants other than methotrexate or cyclosporine.12 Acute GvHD has been grouped into stages from I to IV based on the cutaneous involvement (subject to the area affected and the degree of blisters or vesicle formation).2

Chronic GvHD Between 60–80% of patients develop chronic GvHD after stem cell transplantation, making it one of the most common complications. The skin is the main organ affected, being involved in more than 90% of cases of chronic GvHD.2,8 The development of chronic GvHD is not always a straight progression from acute GvHD. The rate of patients who develop chronic GvHD without any preceding acute GvHD is between 25–35%, and 20–30% of patients with acute GvHD will not go on to develop chronic GvHD.13 Dermatologists distinguish two types of chronic GvHD: lichenoid chronic GvHD (that presents early in the clinical course) and sclerodermatous chronic GvHD (that presents later in the course of chronic GvHD).4 Both lichenoid and sclerodermatous chronic GvHD have very different characteristics at a clinical and histological level, therefore responding differently to treatment.4,14,15 With respect to the evolution of chronic GvHD, the sclerodermatous type is preceded by the lichenoid type in only 40% of patients, and conversely, patients with lichenoid chronic GvHD may not necessarily evolve into the sclerodermatous phase.14,16 From an immunopathological perspective, both lichenoid and sclerodermatous GvHD seem different.15 The outcome for both forms of chronic GvHD differs14,15,17 and the treatments that are administered to patients have different outcomes in lichenoid and sclerodermatous GvHD.4 A set of criteria has recently been developed to aid in the diagnosis of chronic GvHD. This takes into account the severity of the disease (assessed by the number of organs involved) and the severity of their involvement.18 Although these criteria regarded muco-cutaneous involvement as one organ, they make no distinction between lichenoid and sclerodermatous diseases. There have been a number of risk factors associated with the development of chronic GvHD, which include a history of acute GvHD, the patients being more than 20 years of age, instances of a HLA mismatch in stem cell donor, a female stem cell donor to a male host and the presence of T-cells in the donor’s stem cells.8 A cytomegalovirus infection in the patient has also been linked to an increased risk of acquiring chronic GvHD.2 © 2014 The Australasian College of Dermatologists

Treatments for cutaneous GvHD Treatment options for cutaneous GvHD have been reviewed elsewhere.4 In summary, the standard approach is to initiate or increase immunosuppressive therapy, usually with systemic corticosteroids as a monotherapy or in combination with cyclosporine, mycophenolate, tacrolimus, sirolimus, anti-thymocyte globulin or monoclonal antibodies. Extracorporeal photophoresis seems to be a promising treatment for GvHD. In two recent reviews extracorporeal photopheresis has achieved complete response (CR) rates of between 31 and 100% for chronic GvHD and between 62 and 100% for acute GvHD.19,20 There are very few adverse effects or increases in infections associated with extracorporeal photopheresis, which lead to it being very well tolerated.19,20 In chronic GVHD some other medications have also been tried such as thalidomide,21,22 imatinib,23 ketotifen24 or etretinate.25 In both acute and chronic GvHD phototherapy has been used as a treatment option.

PHOTOTHERAPY FOR THE TREATMENT OF CUTANEOUS GvHD Two areas of the UV spectrum have been utilised in the treatment of cutaneous GvHD: UVA (320–400 nm) and UVB (280–320 nm). Due to the low energy of UVA radiation this treatment is usually combined with the photosensitiser psoralen to produce a therapy known as PUVA. This combination is used to treat a range of dermatological conditions that includes psoriasis, atopic eczema, lichen planus, localised scleroderma and cutaneous T-cell lymphoma. Recently, a range of UV radiation between 340 and 400 nm, termed UVA1, has been used with success to treat skin diseases such as atopic dermatitis, localised scleroderma and other T-cell derived conditions.5 UVB radiation can be used as either broadband UVB (280–320 nm, BBUVB) or narrowband UVB (311–312 nm, NBUVB) and has been commonly used in the treatment of dermatological diseases such as psoriasis.5

Mechanism of action The use of phototherapy for the treatment of GvHD skin conditions is believed to produce outcomes such as apoptosis and antiproliferative effects on cells (e.g., T lymphocytes) and causes immunomodulation by influencing cell activation, antigen presentation and cytokine release.26–28 The specific effects that phototherapy induces vary by the condition of the host, the duration of exposure and the dose administered. The mechanisms of action of phototherapy in the treatment of GvHD are not yet understood and the effects of UV radiation on the skin have been reviewed extensively.29,30

Clinical effect of phototherapy in GvHD Many case studies have reported that different forms of phototherapy have produced some benefit to patients with GvHD. However, these studies included very few

Phototherapy treatment Table 1

3

The outcomes of treatment for phototherapy for acute cutaneous graft versus host disease (GvHD)

Patients (n)

Results on cutaneous disease (%)

Mean follow-up period

Systemic disease present (patients)

Treatment

Prophylactic steroids

UVA131

Yes

70

70% CR, 24% PR

18 months

19

UVA132

Yes

7

70% CR, 30% NR

9 months

0

PUVA33

Yes

103

Immunosuppression was reduced in 51%



PUVA34

Yes

20



NBUVB35

Yes

10

75% experienced reduced severity of GvHD and quantity of steroid use 70% CR 30% PR

NBUVB36

Yes

14

57% CR 21% PR

6 months



7

4–18 months



7

Notes Response was seen after a median of five sessions. Three cases of carcinoma developed, no adverse effects were seen with the use of voriconazole. 15% of patients died due to relapse after a median of 5 months. No relapse was noted in the median follow-up period of 9 months. No side-effects were noted. A CR was achieved by 70% of patients in 4 weeks. Oral psoralen. 92% of patients developed chronic GvHD. 50% of patients starting PUVA required additional therapy, including steroids. One patient with a history of squamous cell carcinoma developed a malignancy after 10 PUVA treatments. 10% of patients developed nausea and vomiting due to the psoralen. Oral psoralen. Nine patients died of relapse, infection or organ-related GvHD. A CR response was achieved in seven patients within 3–5 weeks after beginning treatment. Two patients died due to intestinal GvHD and one died after relapse once treatment was stopped. The median length of the NBUVB therapy was 15 treatments over 43 days. Of the CR patients three developed chronic GvHD at 6 months after therapy. One patient had a phototoxic reaction and had to stop therapy for 10 days. One patient presented with a basal cell carcinoma at the last known check-up.

CR, complete response; NBUVB, narrowband UVB, NR, non-responder; PR, partial responder.

participants. Our search strategy included searching online journal databases for studies that had been undertaken on phototherapy for the treatment of GvHD. Once all the studies had been found, journal articles that had fewer than five patients were excluded to decrease reporting bias. The following is an analysis of the studies that were found to be appropriate.

Acute GvHD PUVA The literature provided two studies that had utilised psoralen and UVA phototherapy in combination to treat acute cutaneous GvHD (Table 1). 33,34 Patients included in the studies ranged from stage I to IV of acute GvHD. Psoralen can be administered orally or in a solution applied to the skin (PUVA bath). There were no cases of a PUVA bath in the treatment of acute cutaneous GvHD in the literature. In the oral treatment regime, the psoralen derivative, 8-methoxypsoralen, was given at a median dose of 0.6 mg/kg taken by the patient 1–2 hours prior to the phototherapy. The

initial dose of UVA was usually between 0.3–0.5 J/cm2 up to a maximum dose of 8.5 J/cm2. The use of the photosensitiser allows the administration of a reduced UVA dose, which in turn reduced the total UVA dose that the patient received over the course of the treatment. Adverse events of the oral treatment were reported for a minority of patients who experienced nausea, vomiting, pruritus, skin irritation, longlasting phototoxicity and dizziness.37 In a few cases antiemetics were given before oral psoralen to counter some of these side-effects. Oral PUVA had a CR of over 50% and was able to reduce the quantity of steroids and severity of the cutaneous GvHD, although one study reported that 92% of patients developed chronic cutaneous GvHD.33 The induction of skin malignancies was reported in one study, where a squamous cell carcinoma was noted in a patient with a history of skin cancer and one patient developed a basal cell carcinoma after 7 years following PUVA treatment.33 UVA1 Two studies were found that utilised UVA1 as a treatment for acute cutaneous GvHD.31,32 The patients included © 2014 The Australasian College of Dermatologists

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KB Garbutcheon-Singh and P Fernández-Peñas

in both studies had a range from I to III of acute cutaneous GvHD. Both studies used a maximum dose of 60 J/cm2, which was administered 3–5 times a week. The results of the studies found a CR rate of 70%, with the rest being either partial responders or non-responders. One issue postulated in the literature is the possibility of phototoxicity in patients taking photosensitising medications such as azithromycin, fluoroquinolones, trimethoprim or voriconazole. In one study patients receiving the antifungal agent voriconazole were treated with UVA doses of up to 40 J/cm2 with no side-effects.31 However another study reported the development of skin neoplasias after UVA treatment, and these included one case of melanoma, one of basal cell carcinoma and one of squamous cell carcinoma. This study reported the length of time between the first administration of phototherapy until neoplastic change as 180 days (melanoma) to 1590 days (squamous cell carcinoma).31 In the other study, the follow-up period was shorter (between 150 and 270 days), which may account for neoplastic changes being seen only in the study that examined a large sample size over a long period of time. Both studies concluded that systemic steroid administration could be reduced after the use of phototherapy.31,32

NBUVB Only two studies were found that reported the outcomes of phototherapy treatment of acute cutaneous GvHD using NBUVB phototherapy.35,36 The patients treated in the study had acute GvHD grades I–III. The patients were treated between twice and five times a week and the amount of radiation they received was determined by their Fitzpatrick skin type and minimal erythema dose. The mean cumulative dose for patients was between 8.636 to 12.2 J/ cm2.35 Both studies produced a CR of over 50% and over 70% of patients received some remission of their lesions. Only one patient over the two studies presented with a basal cell carcinoma at the last known check-up.

Chronic GvHD PUVA Three studies were found to use oral psoralen with UVA phototherapy (Table 2). 37,39,40 Two studies were performed using a PUVA bath to treat chronic GvHD.42,43 A PUVA bath is an alternative to oral psoralen, which has been reported to produce systemic side-effects (nausea, vomiting and dizziness) in some patients and the bath is also preferable in patients suffering severe liver impairment. Compared to oral administration a PUVA bath can be quite laborious. The technique involves immersing the patient in a solution of psoralen (0.5 mg/L at 30–37°C) for 20 minutes prior to exposure to UVA radiation. The side-effects noted in the oral psoralen studies were not seen in the studies utilising PUVA-bath techniques. Although when the PUVA bath was combined with the retinoid isotretinoin (10–20 mg daily) (as the related retinoid, etretinate, was found to improve sclerodermatous GvHD25) skin ulcers were prevalent through the early stages of phototherapy.43 There were mixed results on its effectiveness in the PUVA studies conducted. They showed a CR of around 40% in all patients © 2014 The Australasian College of Dermatologists

taking oral psoralen, but more than 70% of patients had a reduction in lesions of some sort. The results for the PUVA bath were similar, with a CR for patients of around 40% but with a beneficial effect on their lesions of over 70% of patients. For chronic GvHD, PUVA treatment was reported to be more effective with the lichenoid form of the disease; with improvement in sclerotic GvHD reported in some instances.5,46 However it was also reported that after the PUVA treatment was ceased the lesions returned.40 UVA1 Three studies were identified that utilised UVA1 in the treatment of chronic cutaneous GvHD. Of these, two were found to have a greater than 50% CR rate and one study showed an overall skin improvement. In the three UVA1 studies a wavelength of 340–400 nm was utilised. The range of doses used for UVA phototherapy was between 50–60 J/cm2. Treatment sessions were given 3–5 times a week. In both the lichenoid and sclerodermatous types of chronic GvHD there was CR rate to the UVA treatment of over 50%. There were a few instances of relapse that occurred in a shorter amount of time for lichenoid GvHD than for sclerodermatous GvHD.3,32 Systemic steroids could be reduced and thus patients experience less toxicity and opportunistic infections.3,32,38 No malignancies were reported in the studies but this may be due to the short follow-up periods and small sample sizes.3,32,38 UVB Two studies were performed on the effect of UVB on chronic GVHD (Table 2).44,45 One study used NBUVB phototherapy and the other used BBUVB. The treatments were administered between 2 and 5 times a week and were reduced as patients showed a positive response to the treatment. From the studies of UVB phototherapy, only one patient with a history of skin malignancies developed skin cancer after 15 months. No other malignancies were noted, but follow-up periods were generally short. NBUVB phototherapy in comparison to oral PUVA therapy was reported as producing a lower risk of developing skin cancer.47 This is an outcome of the fewer treatment sessions required and hence the lower cumulative doses received by patients to reach clearance from the disease. This is one reason why UVB phototherapy is argued to be superior to PUVA therapy when taking into account long-term carcinogenicity.36 Only one study represented the results with a CR that was 75%. The other only presented the clinical response. In both studies all patients received some relief from their symptoms, from the reduction of pruritus to the complete clearance of skin lesions.44,45

Side effects Phototherapy has a number of well-known side-effects that apply to the GvHD population.48,49 It has been seen that GvHD by itself increases the risk of developing basal cell carcinoma, squamous cell carcinoma and melanoma.50,51 This may be further increased by the use of phototherapy in a population that is immunosuppressed and it is usually treated with systemic immunosuppressants,52–54 although

Phototherapy treatment Table 2

5

The outcomes of treatment for phototherapy for chronic cutaneous graft versus host disease (GvHD) Results on cutaneous disease

Mean follow-up period

Systemic disease (patients)

Treatment

Prophylactic steroids

UVA132

Yes

10 (3 lichenoid, 7 sclerodermoid)

60% CR, 30% PR

14 months

0

UVA13

Yes

9 (4 lichenoid, 5 sclerodermoid)

56% CR 44% PR

18 months

6

UVA138

Yes

5 (5 sclerodermoid)





PUVA39

Yes

7 (6 lichenoid, 1 sclerodermoid)

Improvement in skin GvHD were seen in all patients 43% CR 29% PR

8–36 months



PUVA40

Yes

7 (6 lichenoid, 1 sclerodermoid)

43%CR 57% PR

18 months

1

PUVA37

Yes

40 (23 lichenoid, 2 sclerodermoid)

40% CR 38% PR



PUVA bath42

Yes

6 (2 lichenoid, 2 sclerodermoid)

50% CR 50% PR

10 months

0

PUVA bath43

Yes

14 sclerodermoid

29% CR 50% PR





UVB44

Yes

10 (5 lichenoid and 5 overlap)

75% CR 25% PR

24 months

2

UVB45

Yes

5 (1 lichenoid, 2 sclerodermoid)

One patient with cutaneous manifestations recovered completely as did one with intraoral GvHD

3 months

4

Patients (n)

Notes No side-effects were noted besides one case of mild erythema. Two patients with lichenoid GvHD relapsed after treatment was tapered (one PR patient) and 10 months after cessation (one CR patient). Steroids were tapered and then withdrawn in six patients. Three patients with sclerodermatous GvHD and two with lichenoid GvHD achieved CR and two patients with lichenoid and two with sclerodermatous GvHD achieved PR. On average, lichenoid GvHD required fewer phototherapy sessions (16) than sclerodermatous GvHD (22) to achieve a result. Two patients with sclerodermatous GvHD relapsed after 5 months but responded to another cycle of treatment. Typically, patients with lichenoid GvHD relapsed within 1 month and required maintenance phototherapy. Prior to UVA1 two patients received PUVA treatment. A positive response was achieved after 4–6 weeks from commencement of UVA1 treatment. Oral psoralen. Two patients had a remission period of 8 months. Four patients died due to sepsis or chronic GvHD. Oral psoralen. One patient developed chronic GvHD from acute GvHD and achieved a PR in 16 days after beginning PUVA therapy. Three patients had a CR between 45 and 62 days after starting PUVA that lasted for at least 12 months. One death was seen in the CR group due to extracutaneous manifestations of GvHD. Three patients with PR achieved this result after 17–26 days. No neoplasms or pre-neoplastic lesions were observed in the 1.5 year follow up. Four patients suffered from nausea and dizziness from the psoralen. Oral psoralen. Study was performed over 14 years. Six patients were included from a previous study.41 13 patients died due to complications of GvHD. One patient developed a basal cell carcinoma. Due to the oral administration of psoralen antiemetics were occasionally required. Severe phototoxicity was seen in three patients and PUVA was discontinued. Improvements in skin lesions were seen after a median of 14 sessions. Two patients experiences erythema and treatment was interrupted. Two patients relapsed a month after treatment had stopped. Nine patients treated with just PUVA bath and five were treated with PUVA bath and isotretinoin. Of the five who were treated with isotretinoin two had a CR and two had a PR. Ten patients formed skin ulcers that subsequently healed. Paediatric patients used. Median number of treatments to response was 29. CR rate given after 1 year. CR of 71% seen in available patients after 2 years. Erythema and pruritus presented in three patients. Three patients with cutaneous and two patients with intra-oral chronic GvHD. Four of the patients receive some benefit from the treatment and had between 31 and 68 treatments. The two patients with sclerodermatous GvHD only received a reduction in pruritus and dryness whereas the one patient with lichenoid GvHD had CR even at 18-month follow up.

29

CR, complete response; NBUVB, narrowband UVB, NR, non-responder; PR, partial responder.

© 2014 The Australasian College of Dermatologists

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KB Garbutcheon-Singh and P Fernández-Peñas

usually the cumulative dose in GvHD is low compared with other skin conditions (e.g. psoriasis). Moreover, GvHD patients are usually multi-medicated and some could be on phototoxic medication (azithromycin, fluoroquinolones, trimethoprim, voriconazole, etc.), so the risks and benefits of ceasing these medications should also be considered. The patient’s skin should be carefully checked before treatment and routinely monitored during the treatment and in longterm follow up.

GvHD, and they may also have other confounding issues like the involvement of organs besides the skin and relapse of the original cancer. An area of interest that has yet to be fully explored is the use of phototherapy in the prevention of GvHD. The use of phototherapy before or just after patients undergo haematopoietic stem cell transplantation could reduce the risk of developing GvHD.56 Overall, phototherapy for the treatment of cutaneous GvHD warrants more investigation as a promising area of research.

USE OF PHOTOTHERAPY IN GvHD Although the studies reviewed here show that phototherapy has some effect in treating both acute and chronic cutaneous GvHD, it is difficult to propose guidelines for the use of phototherapy in GvHD. For patients in whom most of the skin is affected, the use of phototherapy presents a viable option to treat steroid-refractory disease when the use of systemic immunosuppressants increase the risk of infection or side-effects, or may also complicate a graft versus leukaemia/tumour response. If patients have systemic involvement, phototherapy could be an adjuvant treatment but immunosuppression should be the mainstay of therapy. It is essential to determine the type of lesion to be treated with light. UVB has a relatively short wavelength so it is absorbed primarily in the epidermis, whereas UVA radiation is able to penetrate the dermis.55 For this reason, sclerodermatous lesions are thought to be better treated with UVA-based treatments, and conversely the more superficial acute and lichenoid type of lesions are thought to respond better to UVB-based treatment. There has been no standardisation of the optimal UV dosage and exposure frequency for phototherapy in cutaneous GvHD. This may be related to the fact that there is a wide variability in the patients’ presentation of the disease and thus treatment needs to be individually tailored. In regards to treatments for GvHD using either UVB or UVA, several studies reported that patients received treatment with a frequency to elicit a positive response, usually taking from two to five times per week.

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CONCLUSION Phototherapy for the treatment of cutaneous GvHD has shown some promising results in case-based studies with a small number of patients. Patients receiving phototherapy were able to reduce the amount of steroids they were taking over the duration of the treatment. This indicates that the three types of phototherapy studied may have a steroidsparing effect that may be important for refractory GvHD. The overall conclusion drawn from all these studies is the need for large controlled studies to provide statistically significant evidence on the effectiveness of phototherapy in the treatment of GvHD. There are still a number of considerations that need to be taken into account on the use of UVA1, PUVA and NBUVB phototherapy. For instance, the optimal time for the initiation of phototherapy has not yet been established. Standardisation of the treatment can be difficult, as patients do not present with one specific type of © 2014 The Australasian College of Dermatologists

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Phototherapy for the treatment of cutaneous graft versus host disease.

Graft versus host disease (GvHD) occurs in half the patients who receive allogenic haematopoietic stem cell transplantation and is a major contributor...
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